R01CA257375

Cancer Immune-Interception for Lynch Syndrome - Abstract

Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC), affecting >1 million Americans. LS is caused by germline mutations in the DNA mismatch repair (MMR) genes. Normal colorectal epithelial cells in LS patients become MMR deficient upon acquisition of a 'second' somatic hit in the alternative allele of the same MMR gene that harbors the germline mutation, thus triggering the accumulation of hundreds to thousands of base-to-base mismatches and insertion-deletion mutations (indels) in microsatellite sequences. These mutations generate frameshift peptides (FSP) that become neoantigens (NEOAG) and stimulate the adaptive immune system. We have reported that LS pre-cancers are immune activated and present strikingly high levels of expression of adaptive immune genes. Therefore, LS patients constitute a well-defined and prevalent population that has the potential to benefit from immune-interception strategies to prevent CRC. We have acquired a substantial amount of genomic data from LS colorectal pre-cancers and tumors to catalog and to identify the most frequent recurrent NEOAG present in these lesions. In addition, we have been studying chemopreventive strategies that could augment the immune response and observed increased activation of the resident immune cells in the colorectal mucosa upon exposure to naproxen, a non-steroidal anti-inflammatory drug (NSAID), from our biomarker analysis of our NCI-sponsored phase IB clinical in LS patients. Furthermore, we have performed a co-clinical trial in a humanized LS mouse model that has observed that peptide vaccination with NEOAG is highly effective in preventing LS CRC with the activity that is further enhanced by its combination with naproxen, thus laying the foundations for this grant proposal. The central hypothesis of this proposal is that naproxen is an immune-modulator that activates resident immune cells in the colorectal mucosa, and these will increase the recognition of NEOAG and activation of resident T-cells eliciting tumor cell killing. To explore this hypothesis, we propose three specific aims:

1. To characterize the immune cell types that are regulated after the administration of chemopreventive naproxen and aspirin in LS patients using single-cell genomics and imaging mass cytometry within a randomized phase II clinical trial;
2. To assess the immunogenicity of candidate shared NEOAG identified LS patients pre-cancers and tumors for personalized immunoprevention using tetramer bound to magnetic beads in ELISPOTS, tetramer stain, and cytotoxicity assays of co-cultured patient-derived organoids and autologous CD8+ T cells;
3. To profile the T cell receptor (TCR) of neoantigen-specific CD8+ T cell clones for tracking tumor immunogenicity in LS patients.

The proposed research will significantly impact the field by developing a combination of a peptide vaccination and an NSAID for immune-interception in hereditary cancers for the first time. The proposal is highly innovative by combining a chemoprevention trial using imaging mass cytometry, single-cell genomics, and systems biology to assess trial endpoints, and using tetramers bound to magnetic beads for positive selections of clones in immunology experiments.

The Univeristy Of Texas M.D. Anderson Cancer Center

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Houston, Texas 770304009 United States

Single Zip Code

Cancer Prevention and Control Clinical Trials Grant Program (R01 Clinical Trial Required) (PAR-18-559)

Amendment Since initial award the total obligations have increased 380% from $692,579 to $3,326,163.